The present invention relates to methods and kits for diagnosing and treating pathologies associated with mental retardation such as nonsyndromic mental retardation (NSMR) and/or infantile bilateral striatal necrosis (IBSN).
Mental retardation affects approximately 1% to 3% of the general population. Defining features of mental retardation include intellectual functioning level (IQ) below 70, significant limitations in two or more adaptive skill areas, and presence from childhood (defined as age 18 or less). Genetic etiologies are found in approximately two thirds of mental retardation cases. An autosomal recessive mode of inheritance may account for nearly a quarter of all individuals with nonsyndromic mental retardation (NSMR). NSMR is the diagnosis of exclusion in mentally retarded individuals who do not have major physical abnormalities, dysmorphism or neurological abnormalities. Biological processes involved in neuronal differentiation, synaptic plasticity, synaptic vesicle cycling and gene expression regulation are considered to be important in the causation of mental retardation.
Although clinical diagnosis of mental retardation can be made using accepted intellectual tests and psychological evaluations, there is a need to develop a conclusive diagnostic test for mental retardation in suspected subjects (e.g., children) and/or for prenatal diagnosis of fetuses in families with affected or unaffected siblings.
While a number of X-linked genes associated with NSMR have been identified, there is a large gap in the knowledge regarding the genetic basis of autosomal mental retardation due to heterogeneity and the absence of clinical criteria for grouping the NSMR families for linkage analysis. Only two autosomal genes, the PRSS12 gene on chromosome 4q26 and the CRBN gene on chromosome 3p26, have been shown to cause autosomal recessive NSMR, each gene in only one family (1, 2). Thus, it is clear that multiple genetic components may play a role in the pathogenesis of NSMR and it is therefore desired to further decipher the entire genetic components causing mental retardation in order to enable accurate diagnosis, prenatal diagnosis and treatment.
In a linkage analysis study performed by Basel-Vanagaite L., et al (3), four consanguineous families with severe autosomal recessive NSMR comprising 10 affected and 24 unaffected individuals were clinically evaluated and the disease locus was mapped on chromosome 19p13.12-p13.2 to an interval of 2.4 Mb, between the loci D19S547 proximally and D19S1165 distally (3). However, to date, no disease-causing mutations were identified in any of the genes reside in this locus. In addition, since the candidate region spans over 2.4 Mb, it was impossible to predict which of the genes in this chromosomal interval might be involved with NSMR.
Infantile bilateral striatal necrosis (IBSN) [MIM 271930] is a neurological disorder characterized by symmetrical degeneration of the caudate nucleus, putamen, and the globus pallidus, with little involvement of the rest of the brain. The clinical features of IBSN include developmental regression, choreoathetosis, dystonia, spasticity, dysphagia, failure to thrive, nystagmus, optic atrophy, and mental retardation. Familial IBSN has been reported, suggesting the presence of an autosomal recessive mode of inheritance. In families with mitochondrial inheritance, mutations in the adenosine triphosphatase 6 gene (complex V) have been described (5, 6).
Straussberg R et al., identified and clinically evaluated six consanguineous families with autosomal recessive IBSN (7). The candidate locus for IBSN was mapped to the chromosomal region 19q13.32-13.41, between the markers D19S596 and D19S867, spanning a 1.2 Mb chromosomal region (8). However, due to the lack of identification of a specific gene causing IBSN, no molecular diagnosis can be performed in suspected individuals or in prenatal diagnosis of fetuses in families with affected or unaffected siblings.
There is thus a widely recognized need for, and it would be highly advantageous to have, a method of diagnosing pathologies associated with mental retardation devoid of the above limitations.